Following vaccination, protective antibodies (serologic memory) persist for decades, and are maintained by the combination of antibody secretion from long-lived plasma cells as well as recurrent differentiation of memory B cells into plasma cells. Although, human blood memory B cells can differentiate into plasma cells in response to various non-specific stimuli and T cell-derived factors, it is unclear whether a unique population of memory B cells contributes to serologic memory in humans. Furthermore, the ability of B cells in the blood to produce these protective antibodies over very long periods of time is not well understood. [unreadable] [unreadable] IL-21 is a protein which is important in determining how immune cells will respond to infection. It has been shown in the past to be important in the responsiveness of many different cell subtypes in the blood called T cells, NK cells and B cells. Most of what is known about this protein has been from studies in mice.[unreadable] [unreadable] From our previous studies, we know that human peripheral blood B cells respond to IL-21. Specifically, IL-21 co-stimulation induces both naive and memory B cells from the blood to differentiate into plasma cells via BLIMP-1 and AID induction. We have now turned our attention to determine if IL-21's ability to induce B differentiation may contribute to 1) the ability to maintain serologic memory and 2) the overproduction of autoantibodies in person's with autoimmune diseases. [unreadable] [unreadable] In our recent studies we have examined how IL-21 may be involved in protective immunity. We have recently found that stimulation with two proteins known to be important in B cell biology, IL-21 and BAFF/BLyS, has a profound ability to activate B cells found in the human spleen to differentiate into plasma cells and produce antibodies. This is a unique finding as these splenic memory IgG+B cells have not been previously studied. In most circumstances, human B cells require engagement of CD40 and/or the BCR to respond with significant plasma cell differentiation. However, these B cells are unique in requiring only signals from T cell-derived IL-21 and dendritic cell-derived BAFF/BLyS for this response. The implications of our results are that these cytokines are capable of inducing splenic memory B cells to produce protective antibodies years after the initial exposure to a pathogen or after immunization, and thus contribute to protective humoral immunity.[unreadable] [unreadable] We have also found that in some patients with autoimmune disease, there are memory B cells in the blood capable of responding to IL-21 and BAFF/BLyS. We believe this has important implication in the etiology of the disease and are currently designing experiments to address this more fully.[unreadable] [unreadable] These results represent a major extension of our previous findings which demonstrated an efficient way to induce Ig production from naove B cells. This was a model of T cell-dependent B cell activation and differentiation. Now, we have detailed analysis of human splenic B cell population which revealed a unique population of marginal zone post-switched memory B cells that are capable of responding solely to the combination of IL-21 and BAFF/BLyS resulting in rapid plasma cell differentiation. Our data suggest that this very well may provide the mechanism whereby antigen independent signals can stimulate the replenishment of serologic memory. These results have implications both for understanding the maintenance of protective antibody responses as well as the persistence of autoantibodies, The implications of these findings are numerous. First, IL-21 and BAFF/BLyS could be used at the time of immunizations with vaccines that are not affected (like TB, HIV and malaria). Second, IL-21 and BAFF/BLyS could be used at the time of immunization in person's immuno-compromised by such disease as HIV or cancer. Third, IL-21 and BAFF/BLyS could be used in immuno-compromised people after immunization to help them produce protective antibodies years after the vaccine. And last, drugs which can block the effect of IL-21 and/or BAFF/BLyS could be used in diseases such as lupus, rheumatoid arthritis and some B cell cancers to limit the amount of antibodies produced.